Palbociclib is a cyclin-dependent kinase (CDK4/6) inhibitor developed by Pfizer Inc. It obtained the qualification of “breakthrough therapy” from the U.S. FDA in April 2013. Because of its good clinical performance in Phase III, in August 2014, Pfizer Inc. submitted an application for going on sale to the U.S. FDA and obtained the prioritized examination qualification, and used it for first-line treatment of advanced breast cancer of estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative (HER2−). Successful research of this drug will provide another important choice for the patients with metastatic breast cancer. As this drug still has no standard translated name in Chinese, the applicant hereby transliterates it to “”.
The chemical name of Palbociclib (I) is: 6-acetyl-8-cyclopentyl-5-methyl-2-[[5 -(1-piperazinyl)-2-pyridinyl]amino]-pyrido[2,3-d]pyrimidin-7 (8H)-one, and its structural formula is:

The PCT patents WO2003062236, WO2008032157, WO2012018540 and WO2012068381 of the original research & development Company as well as documents such as Page 2388-2406, Vol. 48, J. Med. Chem., 2005 all have reported the synthetic methods of Palbociclib. Its preparation mainly has two synthetic routes.

The first route takes intermediate A (parent nucleus) and intermediate B (side chain) as the raw materials, and obtains Palbociclib (I) through the reactions such as substitution reaction, Wittig olefination, acid hydrolysis (rearrangement) and de-protection.

The second route obtains Palbociclib (I) through the reactions of the changed intermediate A′ (parent nucleus) and intermediate B (side chain) and then through 6-position modification and de-protection.
Through analysis of the above two synthetic routes, the main difference between them is the difference in 2-position substituent groups of intermediates A and A′ (parent nucleus). The intermediate A in Route 1 is 2-halogen (chlorine), and the intermediate A′ in Route 2 is 2-methylsulfinyl group; obviously, the selective difference between 2-methylsulfinyl group and 6-halogen (bromine) in the intermediate A′ is greater than the selective difference between two halogens (chlorine and bromine) in the intermediate A, so the synthesis design in Route 2 avoids a competitive side reaction caused due to two halogens with similar reactivity in Route 1, and greatly improves reaction yield and product purity. However, synthesis of the core intermediates A and A′ (parent nucleus) is relatively complex no matter for Route 1 or Route 2. Its main raw materials 2,5,6-trisubstituted pyrimidine rings are hard to come by, and there are disadvantages such as various reaction steps and complex side reactions, which greatly limits industrial production of this drug.

With respect to the defects of the current processes, developing a simple and direct, economic and environment-friendly preparation technology with high quality, particularly seeking a process technology that is adaptable to the industrialized production, is of great realistic significance to the improvement of the drug's economic and social benefits.